CHIRAL AUXILIARIES

• US 20130178612A1
• Filed: 09/22/2011
• Published: 07/11/2013
• Est. Priority Date: 09/24/2010
• Status: Active Grant

• Current Assignee: WAVE Life Sciences Ltd.
• Original Assignee: Chiralgen, Ltd.
• Inventors: Wada, Takeshi, Shimizu, Mamoru
• Granted Patent: US 10,428,019 B2
• Time in Patent Office: Days
• US Class Current: 536/23.1
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/62 Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
• CPC Class Codes: C07D 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 211/44 attached in position 4
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 217/24 Oxygen atoms
• CPC Class Codes: C07D 221/10 Aza-phenanthrenes
• CPC Class Codes: C07D 221/18 Ring systems of four or more rings
• CPC Class Codes: C07H 1/00 Processes for the preparation of sugar derivatives
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
• CPC Class Codes: C07H 21/02 with ribosyl as saccharide radical
• CPC Class Codes: C07H 21/04 with deoxyribosyl as saccharide radical

Abstract

Chiral auxiliaries useful for efficiently producing a phosphorus atom-modified nucleic acid derivative with high stereoregularity, and compounds represented by the following the general formula (I) or the general formula (XI) for introducing the chiral auxiliaries.

Claims

1. A compound represented by the following general formula (I):

2. The compound or a salt thereof according to claim 1, wherein R¹ and R² are hydrogen atom or an alkyl group, R³ is phenyl group, R⁴ and R⁵ are hydrogen atom or an alkyl group, and Y is —

C(R⁶)(R⁷)—

(R⁶ and R⁷ are independently hydrogen atom or an alkyl group, and when R⁷ represents an alkyl group, R⁷ may bind with the phenyl group represented by R³ to form a ring), o-phenylene group, or naphthalene-1,2-diyl group.

3. The compound or a salt thereof according to claim 1, which is represented by any of the following structural formulas.

4. A nucleic acid derivative, wherein a chiral auxiliary represented by the following general formula (II):

5. A nucleic acid derivative represented by the following general formula (III):

6. A nucleotide derivative represented by the following general formula (IV):

7. A method for preparing a nucleic acid derivative, which comprises the following steps:

(a) the step of reacting a nucleic acid derivative represented by the following general formula (V);

8. The method according to claim 7, wherein 3% dichloroacetic acid (DCA) in dichloromethane is used for the acidic condition in the step (c).

9. The method according to claim 7, wherein, as the modification of phosphorus atom, a group represented by X (X represents an alkylthio group which may have a substituent, an alkenylthio group which may have a substituent, an alkynylthio group which may have a substituent, an arylthio group which may have a substituent, thiol group, an alkoxy group which may have a substituent, —

BH₃, —

Se⁻

, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent, an acyl group which may have a substituent, or —

N(R¹¹⁶)(R¹¹⁷) (R¹¹⁶ and R¹¹⁷ independently represent hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or an aryl group which may have a substituent) is introduced on the phosphorus atom.

17. The method according to claim 8, wherein, as the modification of phosphorus atom, a group represented by X (X represents an alkylthio group which may have a substituent, an alkenylthio group which may have a substituent, an alkynylthio group which may have a substituent, an arylthio group which may have a substituent, thiol group, an alkoxy group which may have a substituent, —

BH₃, —

Se⁻

, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent, an acyl group which may have a substituent, or —

N(R¹¹⁶)(R¹¹⁷) (R¹¹⁶ and R¹¹⁷ independently represent hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or an aryl group which may have a substituent) is introduced on the phosphorus atom.

10. A compound represented by the following general formula (XI):

11. The compound or a salt thereof according to claim 10, wherein R¹⁰¹ and R¹⁰² are hydrogen atom or an alkyl group, R¹⁰³ is cyano group, and Z is —

C(R¹⁰⁴)(R¹⁰⁵)—

(R¹⁰⁴ and R¹⁰⁵ are hydrogen atom or an alkyl group.

12. The compound or a salt thereof according to claim 10, wherein R¹⁰¹ and R¹⁰² are hydrogen atoms, R¹⁰³ is cyano group, and Z is —

C(R¹⁰⁴)(R¹⁰⁵)—

(R¹⁰⁴ and R¹⁰⁵ are hydrogen atoms).

13. A nucleic acid derivative, wherein a chiral auxiliary represented by the following general formula (XII):

14. A nucleic acid derivative represented by the following general formula (XIII):

15. A nucleotide derivative represented by the following general formula (XIV):

16. A method for preparing a nucleic acid derivative comprising the following steps:

(a) the step of reacting a nucleic acid derivative represented by the following general formula (XIII′

);